ABSTRACT: Lung cancer is the leading cause of cancer-related death in
males and females in the United States. Most patients have advanced disease at
diagnosis. Chemotherapy is the treatment of choice for patients with good
performance status. Progress in the management of patients with advanced disease
has been slow, and platinum-based combinations result in a small survival
benefit. The topoisomerase I inhibitors are active as single agents and in
combination with platinums in non-small-cell lung cancer. Nonplatinum-based
doublet combinations are beginning to be explored in an attempt to reduce
toxicity and improve efficacy. Data available on some of the nonplatinum
doublets that include topoisomerase I inhibitors suggest that these regimens
provide efficacy equal to that achieved with platinum-based doublets. This
article reviews the topoisomerase I-inhibitor nonplatinum combinations in the
management of advanced non-small-cell lung cancer. [ONCOLOGY 16(Suppl
9):25-31, 2002]

Efficacy data from studies of various combinations of platinum
with other cytotoxic drugs in non-small-cell lung cancer suggest that a
therapeutic plateau has been reached. The Eastern Cooperative Oncology Group (ECOG)
1594 randomized study demonstrated no efficacy differences among four different
platinum-based chemotherapy doublets.[1] Similar results were recently reported
for a European phase III trial.[2] The development of non-platinum-containing
combinations offers a strategy to lower toxicity and maintain efficacy in the
treatment of non-small-cell lung cancer.

The taxane plus gemcitabine (Gemzar) doublets have been the most
explored nonplatinum combinations in non-small-cell lung cancer, and a recent
European Organization for Research and Treatment of Cancer (EORTC) trial
compared two platinum-containing doublets (standard arm of cisplatin/paclitaxel
or cisplatin/gemcitabine) to the gemcitabine plus paclitaxel combination.[3]
Although survival among the three treatment arms was not significantly
different, there was a trend toward worse survival with the nonplatinum
combination. This disappointing result should not hamper additional studies with
other nonplatinum combinations, however.

Several topoisomerase I inhibitors have been studied in patients
with non-small-cell lung cancer. One such agent is 9-aminocamptothecin (9-AC),
which is a synthetic analog of camptothecin. In a phase II study conducted by
Vokes et al, patients with stage IIIB or IV non-small-cell lung cancer with
measurable disease received 9-AC at 1,416 µg/m²/d × 3 by continuous
intravenous infusion followed by granulocyte colony-stimulating factor (G-CSF [Neupogen])
support.[4] The 9-AC dose was decreased to 1,100 µg/m²/d after the first 13 of
58 accrued patients had been treated. Cycles were repeated every 14 days.

Five patients (8.5%) achieved a partial response. Median time to
disease progression was 2.3 months, and median survival for the entire study
population was 5.4 months with a 1-year survival rate of 30%. In another study
by Vokes and colleagues, non-small-cell lung cancer patients received 9-AC in
a different administration schedule, ie, 25 µg/m²/h for 120 hours (3,000
µg/m²
over 5 days), given for 2 consecutive weeks of a 3-week cycle.[5] Results were
again disappointing, with only 1 of 12 patients responding. The authors
recommended no additional studies with 9-AC in non-small-cell lung cancer.

Exatecan mesylate, a synthetic water-soluble topoisomerase I
inhibitor, is active as single-agent therapy for non-small-cell lung cancer
patients. In a small phase II trial, 23 patients with previously untreated,
advanced (11 stage IIIB, 12 stage IV) non-small-cell lung cancer received
exatecan at 0.5 mg/m² IV over 30 minutes daily for 5 days, every 3 weeks.[6]
Among 16 evaluable patients, 18% responded; survival data were not reported.
Further development of this compound in non-small-cell lung cancer may be
warranted.

Karenitecin is a highly lipophilic topoisomerase I inhibitor
that has undergone limited phase II testing. The Cancer and Leukemia Group B (CALGB)
is conducting an ongoing phase II trial of this semisynthetic camptothecin in
previously treated non-small-cell lung cancer patients. The karenitecin dose
is 1 mg/m²/d administered over 60 minutes by IV infusion for 5 consecutive days,
with cycles repeated every 3 weeks. This dose and schedule was identified as the
maximum tolerated dose in a previous phase I trial, in which 14 patients (4
pancreatic, 4 colorectal, and 6 other cancers) received a total of 32 (range: 1-9,
median: 2) treatment cycles.[7]

The topoisomerase I inhibitors irinotecan (CPT-11, Camptosar)
and topotecan (Hycamtin) are available commercially in the United States.
Although these agents possess similar antitumor mechanisms of action, their
single-agent activity in non-small-cell lung cancer differs (Tables 1 and2).[8-17] As shown in Table
2, the absence of topotecan single-agent activity in
non-small-cell lung cancer apparently did not compromise median survival.

The combination of irinotecan and cisplatin has been studied in
two phase III trials in non-small-cell lung cancer patients.[18,19] In both
trials, irinotecan at 60 mg/m² was administered on days 1, 8, and 15, and
cis-platin at 80 mg/m² on day 1. This regimen was compared with the standard
regimen of cisplatin at 80 mg/m² given on day 1 plus vindesine (Eldisine) at 3
mg/m² on days 1, 8, and 15. One of the trials also included a third arm
consisting of single-agent irinotecan at 100 mg/m² on days 1, 8, and 15. As
shown in Table 3, survival results for the irinotecan/cisplatin combination
compared with vindesine/cisplatin differed in the two trials. No phase III trial
results of topotecan in non-small-cell lung cancer are available; phase II
data with topotecan/platinum combinations are emerging in this disease (Table
4).[20,21]

Studies of non-platinum-containing combination regimens that
include topoisomerase I inhibitors plus gemcitabine or microtubule poisons have
been conducted or are under way in patients with non-small-cell lung cancer.
Several of these studies are reviewed herein.

Preclinical data using breast and lung cancer cell lines
suggested that gemcitabine and irinotecan exhibit synergistic activity when used
in combination.[22] Isobologram analysis revealed that the combination exerted
synergy over a wide range of concentrations in the MCF-7 and SCOG cell lines.
Combination index analysis also indicated that at low concentrations,
combinations of gemcitabine and irinotecan showed synergistic growth-inhibitory
effects on MCF-7. In SCOG cells, however, combination index analysis showed
synergy at concentrations of gemcitabine and irinotecan > 1 µM but
antagonism at concentrations < 1 µM.

Three phase I studies of three different schedules of the
gemcitabine/irinotecan combination have been performed. Rocha Lima et al[23]
studied the administration of both drugs on days 1 and 8 of each 21-day cycle.
Gemcitabine was administered first at a fixed dose of 1,000 mg/m² over 30
minutes followed by escalating doses of irinotecan given over 90 minutes. The
initial irinotecan dose was 50 mg/m² with subsequent cohorts tested at 75, 100,
and 115 mg/m². Nineteen patients with a variety of solid tumors were accrued.
The maximum tolerated dose was determined to be 1,000 mg/m² of gemcitabine and
100 mg/m² of irinotecan, both given on days 1 and 8. The dose-limiting toxicity
was grade 3 diarrhea in two of seven patients at the 115-mg/m² irinotecan dose.

O’Reilly and colleagues reported the results of a phase I
trial of the gemcitabine/irinotecan combination, with both drugs administered on
days 1, 8, and 15 in every 28-day cycle.[24] The gemcitabine dose was fixed at
1,000 mg/m² given over 30 minutes. Irinotecan doses were escalated in four
cohorts from a starting dose of 45 mg/m², to 60, 80, and 100 mg/m² over 90
minutes. When gemcitabine was given first immediately followed by irinotecan,
the dose-limiting toxicities consisted of diarrhea, nausea and vomiting,
neutropenia, and fatigue.

When irinotecan was given first immediately followed by
gemcita-bine, the dose-limiting toxicities were neutropenic fever and diarrhea.
The maximum tolerated dose with both sequences was gemcitabine at 1,000 mg/m²
and irinotecan at 60 mg/m². Preliminary pharmacokinetic assessments demonstrated
no differences between the two sequences in the levels of gemcitabine, the
uridine metabolite of gemcitabine, irinotecan, and irinotecan metabolites SN-38
and SN-38G.

Alberts et al studied both drugs administered on days 1, 8, 15,
and 22, with cycles repeated every 6 weeks in 26 patients with refractory solid
tumors.[25] The dose-limiting toxicity was hematologic toxicity in two of six
patients receiving gemcitabine at 1,000 mg/m² and irinotecan at 125 mg/m², and
the recommended phase II doses for the agents in combination were gemcitabine at
1,000 mg/m² and irinotecan at 100 mg/m². The dose intensity must be carefully
analyzed in the follow-up phase II trials. One would anticipate treatment
omissions on day 15 of therapy due to diarrhea and/or myelosuppression with this
schedule at these doses.

Several phase II trials of the gemcitabine/irinotecan
combination have been conducted in patients with non-small-cell lung cancer. A
randomized phase II trial CALGB 39809 is assessing two nonplatinum combinationsirinotecan/gemcitabine
and docetaxel (Taxotere)/gemcitabine (Figure 1). Efficacy results were presented
at the 2002 annual meeting of the American Society of Clinical Oncology (ASCO).
The efficacy results for gemcitabine and irinotecan included a response rate of
12.8%, with 48.7% stable disease, a 7.9-month median survival, and a 1-year
survival rate of 16%. For the docetaxel/gemcitabine arm, the response rate was
23.1%, with 41% stable disease, a 12.8-month median survival, and a 1-year
survival rate of 55%. Both doublets were well tolerated, which may reflect the
administration schedule, ie, both agents given on days 1 and 8, every 21 days.
Toxicity results are summarized in Tables 5 and6.

Preclinical studies with human lung cancer cell lines H460 and
H322 demonstrated an additive growth inhibition (and concentration- and
time-dependent apoptotic effects) when another topoisomerase I inhibitor
topotecan was combined with gemcitabine.[26] Based on these preclinical data,
two phase I studies of the gemcitabine/topotecan combination were conducted.
Edelman et al[27] determined the maximum tolerated dose of topotecan to be 1
mg/m²/d IV over 30 minutes daily for 5 days, and that of gemcitabine to be 1,000
mg/m² over 30 minutes on days 1 and 15, in 28-day cycles. After a
dose-escalation study, Rainey and colleagues[28] recommended phase II doses of
topotecan at 0.75 mg/m²/d over 30 minutes for 5 days and gemcitabine at 400
mg/m² on days 1 and 5, every 21 days. Neutropenia and thrombocytopenia were the
dose-limiting toxicities.

In a preliminary report from US Oncology, the combination of
gemcitabine and topotecan resulted in a median survival time of 7.3 months in 53
advanced non-small-cell lung cancer patients with good performance status (0
or 1).[29] Doses were topotecan at 1 mg/m²/d IV over 30 minutes for 5
consecutive days, and gemcitabine at 1,000 mg/m² days 1 and 15, on an
every-28-day cycle. Grade 3/4 toxicities included neutropenia (49% of patients),
anemia (15%), and thrombocytopenia (9%). The response rate was 17% (all partial
responses), and 22% of patients had stable disease. Final results were presented
at ASCO’s 2002 annual meeting.

At least one phase II study of second-line topotecan plus
gemcitabine in non-small-cell lung cancer has been conducted. Cole and
colleagues[30] studied topotecan at 0.75 mg/m²/d IV days 1 to 5 and gemcitabine
at 400 mg/m² days 1 and 5, given every 21 days to 32 patients with refractory
non-small-cell lung cancer. A total of four patients (13%) had partial
responses, and seven (22%) had stable disease for at least four cycles. Median
survival time was 7 months. One year from the initiation of topotecan and
gemcitabine treatment, 20% (5/25) of patients were still alive. Nonhematologic
toxicity was mild. After the first treatment cycle, grade 4 neutropenia and
thrombocytopenia was observed in 16% and 9% of patients, respectively.
Hematologic toxicities for all cycles, to our knowledge, have not been reported.